The principal objective of the overall proposed research is to further our understanding of the regulation or control of human neutrophil function in the inflammatory process. The main direction or hypothesis is to be tested is that common intracellular messenger agents (cyclic GMP and cyclic AMP) possess the capacity to modulate not just one but several complementary functions of human neutrophils, such as lysosomal enzyme secretion, phagocytosis, chemotaxis, cellular adherence to immune complexes, and antibody-dependent cellular cytotoxicity. The idea that common "signals" mediated several different but complementary functions of a given cell type in a complicated pathologic process would greatly simplify our understanding of the bioregulation of cell function in general. The goals or specific aims of the project for this first year of the renewal grant were: (a) to ascertain whether cyclic GMP and cyclic AMP are second messengers in expressing the effects of various tissue hormones and immune stimulants on certain neutrophil functions other than secretion, such as those listed above; (b) to identify and characterize the enzyme guanylate cyclase, which is responsible for the biosynthesis of cyclic GMP, in purified human neutrophils and to determine the influence of immune stimulants, tissue hormones and pharmacologic agents (nitric oxide) on the activity of this enzyme; (c) to further study the properties of adenylate cyclase from purified human neutrophils, and to examine the relationships between adenylate and guanylate cyclase activities in the presence of immune reactants, tissue hormones and other pharmacologic agents; (d) to study in greater detail the possible mechanisms by which levamisole, imidazole, methylprednisolone, arachidonic acid, and lipoxygenase products affect neutrophil cyclic nucleotide levels and function (primarily lysosomal enzyme secretion); (e) to study the precise relationship between cyclic GMP and cell function in neutrophils, platelets and coronary artery, by using nitric oxide as the pharmacologic intervention.